title: Beneficial effects of pioglitazone on atrial structural and electrical remodeling in vitro cellular models.
abstract: It has been demonstrated that atrial remodeling contributes toward atrial fibrillation (AF) maintenance and angiotensin II (AngII) is involved in the pathogenesis of atrial remodeling. Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists have been shown to inhibit atrial remodeling. However, the underlying mechanisms are poorly understood. In the present study we investigated the regulating effects of PPAR-γ agonist on AngII-induced atrial structural and electrical remodeling in vitro cellular models. The effects of pioglitazone on AngII-induced connective tissue growth factor (CTGF) expression and cell proliferation were assessed in primary-cultured mouse atrial fibroblasts. The influences of pioglitazone on AngII-induced L-type calcium channel (ICa-L) α1c expression and current density were evaluated in atrial myocytes (HL-1). Pioglitazone attenuated AngII-induced CTGF expression and proliferation in atrial fibroblasts, and pioglitazone also inhibited the expression or phosphorylation of AngII-induced transforming growth factor-β1 (TGF-β1), tumor necrosis factor receptor associated factor 6 (TRAF6), TGF-β-associated kinase 1 (TAK1) and Smad2/3. In HL-1 cells, pioglitazone suppressed AngII-induced ICa-L α1c expression and current density as well as CAMP responsive element binding protein (CREB) phosphorylation. Besides, pioglitazone inhibited AngII-induced production of AngII type I receptor (AT1R) and downregulation of PPAR-γ in both atrial fibroblasts and HL-1 cells. In conclusion, Pioglitazone suppresses AngII-induced CTGF expression and proliferation in atrial fibroblasts, which might be at least in part related with its inhibitory effects on TGF-β1/Smad2/3 and TGF-β1/TRAF6/TAK1 signaling pathways. Moreover, pioglitazone also attenuates AngII-induced ICa-L remodeling in HL-1 cells, which might be at least in part associated with its inhibitory effect on CREB phosphorylation. It is suggested that PPAR-γ agonist may have potential applications in preventing atrial remodeling.
authors.affiliation: Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China; Department of Cardiology, Minhang hospital, Ruijin Hospital Group, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Gu
authors.forename: Xu
authors.initials: X
authors.lastname: Liu
authors.forename: Quan-Xing
authors.initials: QX
authors.lastname: Wang
authors.forename: Meng
authors.initials: M
authors.lastname: Guo
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: Zhi-Ping
authors.initials: ZP
authors.lastname: Song
authors.forename: Da-Dong
authors.initials: DD
authors.lastname: Zhang
mesh_terms: D000804:Angiotensin II; D000818:Animals; D064752:Atrial Remodeling / Q000187:drug effects*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D055724:Electrophysiological Phenomena; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006325:Heart Atria / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology*; D015640:Ion Channel Gating / Q000187:drug effects; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D047495:PPAR gamma / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D000077205:Pioglitazone; D021122:Protein Subunits / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D000804:Angiotensin II; D002316:Cardiotonic Agents; D017362:Cyclic AMP Response Element-Binding Protein; D020930:MAP Kinase Kinase Kinases; D047495:PPAR gamma; D010768:Phosphoserine; D000077205:Pioglitazone; D021122:Protein Subunits; D044140:Receptor, Angiotensin, Type 1; D051785:Smad Proteins; D048029:TNF Receptor-Associated Factor 6; D045162:Thiazolidinediones; D053773:Transforming Growth Factor beta1; D000099151:MAP Kinase Kinase Kinase 7
keywords: Angiotensin II; Atrial electrical remodeling; Atrial structural remodeling; PPAR-γ agonists; Signaling pathway